Abstract CT117: Synergism between inhibitors of the EGFR-RAS-RAF-MEK pathway and the WNT pathway
Authors: Jinjin Cai, Andrew Dorr, Laurie Rosenstein, Jim Labdon, Xiaojuan Li, Hang Zhou, Yanyuan Zhou, Wangjun He, Qiuping He, Xiaoyan Huang, Aparna R. Parikh, Marios Giannakis, Michael An
Journal: Cancer Research (2023)

Abstract Background Inhibitors of the EGFR-RAS-RAF-MEK (MAPK) pathway have been successfully developed to treat cancers. However, many patients do not benefit from these inhibitors due to primary or acquired resistance. In colorectal cancer (CRC), resistance to inhibitors of the MAPK pathway is especially prominent, reflected by low response and short survival. Reactivation of MAPK signaling is a common mechanism of acquired resistance in CRC. WNT pathway is hyperactivated in the majority of CRC patients due to genetic alterations of several genes involved in WNT signaling, e.g., APC, CTNNB1, RSPO and RNF43. Cooperation between RAS-RAF and WNT signaling drives the carcinogenesis of CRC. Concomitant blockade of WNT signaling has been shown to impede the emergence of BRAF inhibitor-resistant clones, thus offering the possibility to overcome acquired resistance. Methods To prove the concept that simultaneous inhibition of the WNT pathway and the MAPK pathway reduces primary or acquired resistance to CRC treatment, we have tested combinations of various inhibitors of both pathways in CRC models, including BRAFV600E ;RSPO3 PDX models, KRASG12C ;RSPO3 cell lines and APC-mutated cell lines with or without KRAS mutations, including KRASG12C ;APC CRC cell lines. We tested MAPK pathway inhibitors, such as cetuximab, selumetinib and cobimetinib (MEK1/2 inhibitors), encorafenib (BRAFV600E inhibitor), and AMG510/sotorasib (KRASG12C inhibitor). Inhibitors of the WNT pathway included a porcupine inhibitor, CGX1321, that blocks the secretion of WNT ligands, currently in clinical development, and a tankyrase inhibitor, CGX11071, that stabilizes AXIN-1/2 and degrades β-catenin. Synergistic effects between inhibitors of the MAPK pathway and the WNT pathway were observed in CRC models in vitro and in vivo. Notably, when CGX1321 was added to encorafenib and cetuximab in CRC PDX models with BRAFV600E and RSPO fusions, a decrease in tumor size (&amp;gt;50%) occurred in two weeks, compared with tumor progression with encorafenib and cetuximab or CGX1321 treatment alone. Notable is the synergy between tankyrase inhibitor CGX11071 and KRASG12C inhibitor AMG510/sotorasib in CRC cell lines with KRASG12C and RSPO fusion (or APC mutations). We launched a phase 1b clinical trial to study the efficacy of CGX1321 in combination with encorafenib and cetuximab in CRC patients with RSPO fusions and BRAFV600E mutations. (NCT02675946). Primary endpoint included safety and RP2D. Secondary endpoints included PK, overall response rate, CR and PR rate, and duration of response by RECIST 1.1 and irRECIST 1.1. The clinical protocol and available data of CGX1321 in combination with encorafenib and cetuximab in CRC patients with RSPO fusions and BRAFV600E mutations will be discussed. Citation Format: Jinjin Cai, Andrew Dorr, Laurie Rosenstein, Jim Labdon, Xiaojuan Li, Hang Zhou, Yanyuan Zhou, Wangjun He, Qiuping He, Xiaoyan Huang, Aparna R. Parikh, Marios Giannakis, Michael An. Synergism between inhibitors of the EGFR-RAS-RAF-MEK pathway and the WNT pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT117.